Neisseria gonorrhoeae causes about 600,000 new infections each year in the United States, with health- care costs approaching 2 billion dollars/year. The costs and human suffering are amplified by the fact that concomitant gonococcal infections appear to facilitate HIV transmission. Gonococci preferentially infect the human urogenital tract, and its ability to enter and transcytose this mucosal surface is a chief cause of pelvic inflammatory disease, tubal infertility, ectopic pregnancy, and chronic pelvic pain. Various surface components, i.e. lipooligosaccharide (LOS) and opacity proteins (Opa) are important in mediating these diseases. Most studies have used tissue culture models to study the role of individual surface components in the pathogenic process, even though it is likely that multiple components are needed and/or are able to act synergistically. The fact that this pathogen manipulates its outer membrane suggests that such modifications are important in pathogenesis. Nothing is known about possible interactions between the surface molecules, because to date, we have lacked bacterial strains that have invariant, defined surfaces. This has prevented us from developing a comprehensive understanding of the pathogenesis of gonococcal disease. The objectives of this proposal are to understand how Opa and LOS function in disease, and determine if these two antigens interact in the pathogenic process. The central hypothesis of the proposed research is that different variants of these surface antigens are important for the various stages of infection. We intend to test our hypotheses by pursuing three specific aims: We will determine how various surface structures promote invasion into different tissue culture cells, we will identify the signaling pathways activated by this interaction, and we will define the cellular responses in host cells that are initiated by gonococcal adherence. The results of our study will allow us to define how LOS and Opa variation contribute to disease pathogenesis. The impact on human health is expected to be significant, because the new knowledge will likely make possible new approaches to the prevention and treatment of gonorrhea.